Central Neural Mechanisms of Itch

瘙痒的中枢神经机制

• 批准号: 8496139
• 负责人: GLENN JOSEPH GIESLER
• 金额: $ 30.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496139
• 关键词: Adverse effects; Affect; Afferent Neurons; Analgesics; Antihistamines; Area; Axon; Brain; Capsaicin; Cathepsins; Cell Nucleus; Cerebral cortex; Chronic; Circumscribed Lesion; Clinical; Complex; Disease; Esthesia; Funding; GABA Antagonists; Glycine; Histamine; Injection of therapeutic agent; Inpatients; Instruction; Insula of Reil; Lateral posterior nucleus of thalamus; Mediating; Methods; Modeling; Monkeys; Morphine; Neuraxis; Neurons; Nociception; Nociceptive Stimulus; Opiates; Pain; Pathway interactions; Patients; Peptide Hydrolases; Population; Posterior Thalamic Nuclei; Primates; Principal Investigator; Process; Production; Pruritus; Public Health; Role; Sensory Process; Site; Skin; Spinal; Spinal Cord; Spinothalamic Tracts; Stimulus; System; Systemic disease; Techniques; Testing; Thalamic structure; Thoracic spinal cord structure; chronic pain; effective therapy; insight; intradermal injection; midbrain central gray substance; neuromechanism; neurophysiology; novel therapeutic intervention; receptive field; research study; response; spinal cord white matter; transmission process; white matter

Itch associated with several conditions can be effectively treated with antihistamines. However itch caused by many conditions, including relatively common dermatological disorders and systemic diseases, can not. These latter types of itch constitute a considerable clinical problem since no effective treatment is currently available. During the previous period of funding, our group has shown that separate populations of primate spinothalamic tract (STT) neurons respond to the itch-producing stimuli intradermal injections of histamine and cowhage, a model of clinically important, non-histaminergic itch. Our results suggest that separate pathways within the CNS carry information regarding histaminergic and non-histaminergic forms of itch. In experiments under Specific Aim 1, we will determine the effects on STT neurons of application of histamine, cowhage, capsaicin, or cathepsin S. These studies will determine whether there are two, or more, distinct pruriceptive pathways within the primate STT. We have also recently found that scratching the receptive fields of STT neurons during a response to histamine inhibited the response for several seconds, mirroring the relief produced by scratching an itchy area of skin. Studies under Specific Aim 2 will determine whether the scratching induced inhibition is dependent solely upon circuitry within the spinal cord or whether there are also important contributions from the brain. Administration of morphine inpatients frequently produces severe itch. This side effect can limit the amount of morphine given to treat chronic pain . Under Specific Aim 3, we will determine whether iontophoretically applied morphine activates pruriceptive and inhibits non- pruriceptive (nociceptive) STT neurons. Our results using antidromic activation techniques revealed that pruriceptive primate STT axons project to several specific nuclei within the posterior thalamus. Under Specific Aim 4, we will record the responses of neurons in these thalamic areas to histamine injections or applications of cowhage. We will identify cortical projection sites of pruriceptive thalamic neurons using antidromic activation. These studies will provide important new information on the processing itch-related information in both the thalamus and cerebral cortex. RELEVANCE (See instructions): The proposed neurophysiological experiments will further our understanding of how itch and pain sensations are mediated by the responses of different types of sensory neurons in the spinal cord and the brain. This will benefit public health by identification of sensory processes in the central nervous system that must be modified pharmacologically in patients suffering from chronic itch or pain.

与几种条件相关的瘙痒可以有效地用抗组胺药治疗。然而瘙痒引起的 由许多条件，包括比较常见的皮肤病和全身性疾病，不能。 这些后一种类型的瘙痒构成相当大的临床问题，因为目前没有有效的治疗方法。 available.在之前的资助期间，我们的研究小组已经证明，灵长类动物的不同种群 脊髓丘脑束（STT）神经元对皮内注射组胺的瘙痒刺激作出反应 和cowhage，一种临床上重要的非组胺能瘙痒的模型。我们的研究结果表明， CNS内的通路携带关于组胺能和非组胺能形式的瘙痒的信息。在 具体目标1下的实验，我们将确定应用组胺对STT神经元的影响， cowhage、辣椒素或组织蛋白酶S。这些研究将确定是否有两个，或更多， 灵长类STT内的免疫感受通路。我们最近还发现， STT神经元在对组胺的反应中抑制了几秒钟的反应，反映了 通过抓挠皮肤上发痒的地方来缓解疼痛。具体目标2下的研究将确定 抓挠诱导的抑制作用仅依赖于脊髓内的回路， 也是大脑的重要贡献。吗啡的管理住院病人经常产生 严重瘙痒。这种副作用会限制吗啡治疗慢性疼痛的剂量。具体目标下 3，我们将确定离子导入应用吗啡是否激活镇痛和抑制非镇痛。 伤害感受性（nociceptive）STT神经元。我们使用逆向激活技术的结果显示， 灵长类STT轴突投射到后丘脑内的几个特定核团。下 具体目标4，我们将记录这些丘脑区域的神经元对组胺注射或 牛栏的应用我们将确定皮质投射部位的丘脑神经元的伤害性使用 逆向激活这些研究将提供重要的新的信息处理瘙痒相关的 丘脑和大脑皮质中的信息。 相关性（参见说明）： 拟议中的神经生理学实验将进一步加深我们对瘙痒和疼痛感觉的理解 由脊髓和大脑中不同类型的感觉神经元的反应介导。这 将通过识别中枢神经系统中的感觉过程来有益于公共健康， 在患有慢性瘙痒或疼痛的患者中的改良的瘙痒。